Pancreatic adenocarcinoma is the fourth leading cause of adult cancer mortality in the United States. The five-year survival rate continues at 1-3% and the median survival after diagnosis is less than six months. At the time of diagnosis, most pancreatic cancer patients present with locally advanced or metastatic disease. Pancreatic cancer is characterized by poor prognosis and lack of response to conventional therapy. Hence, pancreatic cancer poses one of the greatest challenges in cancer research. A genetic profile for pancreatic cancer is emerging based on the most frequently detected mutations in this disease. For example, the mutational activation of K-ras is an early event in pancreatic carcinogenesis and has been detected in 80-95% of pancreatic cancers;and inactivation of p16/Ink4a/Arf and p53 tumor suppressor genes can be identified approximately 50-75% of pancreas cancers. However, significant gaps still exist in our understanding of how such genetic alterations affect pancreatic cancer development and progression. For example, although NF-?B is constitutively activated in nearly 70% human pancreatic cancer tissues and most pancreatic cancer cell lines, it is still unclear whether constitutive NF-?B activation is required for tumorigenic transformation of pancreatic cells or progression to metastatic pancreatic cancer in vivo, and whether the molecular pathogenesis of pancreatic cancer can be recapitulated by NF-?B constitutive activation in combination with other signature mutations in genetic engineered mouse models. Autocrine stimulation of pro-inflammatory cytokine IL-1 activates NF-?B in pancreatic cancer cell lines, which in turn induces expression of IL-1, I?B? and its downstream target genes that are essential for inflammatory responses, angiogenesis, apoptosis, tumorigenesis, and metastasis. However, it is unclear how constitutive NF-?B activation is initially triggered. Thus, the underlying mechanisms by which constitutive NF-?B activation is induced in vivo also remain to be further investigated. Transforming growth factor-? activating kinase 1 (TAK1) is overexpressed in pancreatic cancer cell lines and specimens. Our preliminary data show that TAK1shRNA completely inhibited constitutive NF-?B activation in pancreatic cancer cells. However, the underlying molecular mechanism of TAK1 overexpression-induced NF-?B activation still remains an area of ongoing study. The long-term goal of our research is to recapitulate the molecular pathogenesis of this disease by establishing mouse models with signature molecular and genetic alterations found in pancreatic cancer, and elucidate the mechanisms for TAK1 overexpression-mediated NF-?B activation. Based on our preliminary results, we hypothesize that overexpression of TAK1 induces constitutive NF-?B activity and NF-?B-mediated pro-inflammatory responses, which in turn promotes development of pancreatic cancer. To test our related hypotheses, three specific aims were proposed: (1) Determine the role of IKK2-mediated NF-?B activation in the development of pancreatic cancer using pancreatic specific IKK2 knockout approach in KrasG12D and KrasG12D/p16/Ink4a compound mutant mice;(2) Determine the function of constitutive NF-?B activity in induction of pancreatic cancer in K-rasG12D I?B?m?Bm?B conditional mutant mice, in which NF-?B is constitutively activated by knocking in mutated ?B enhancer in I?B? promoter to inhibit the I?B?-mediated negative feedback regulation of NF-?B;(3) Determine whether TAK1 overexpression promotes K-rasG12D-induced tumorigenesis using immortalized pancreatic ductal epithelial cells and tissue-specific transgenic mice and elucidate the mechanisms by which TAK1 overexpression induced NF-?B activation. The findings from our proposed study will provide an insight into the regulation of MAP3K activation in induction of inflammatory responses and pancreatic cancer. Most importantly, this study may discover novel molecular targets for improving the treatment for pancreatic cancer.